Desmosomes are intercellular adhesive junctions that play pivotal roles in maintaining tissue architecture and function as illustrated by the development of several skin fragility and hair abnormality conditions when they are impaired. Desmogleins (Dsg) are the Ca2+dependent adhesion components of desmosomes and Dsg1, 3, and 4 are the target molecules in several human autoimmune, infectious, and inherited diseases. Thus, the roles of these proteins in cell-cell adhesion, skin barrier function, and hair follicle development are well established. However, whether these desmogleins can mediate intracellular signal transduction pathways is poorly understood. Studies of Dsg2 null mice attest to the importance of Dsg2 during embryonic development and in stem cell growth and survival. Furthermore, Dsg2 is overexpressed in certain epithelial malignancies including squamous cell carcinomas (SCC) suggesting its role in cell proliferation and differentiation that favor of tumor development. However, it is unknown whether - and if so how - Dsg2 contributes to the malignant phenotype of SCC. Consequently we established an in vivo transgenic mouse model overexpressing Dsg2 in the epidermis. Preliminary results demonstrate that ectopic expression of Dsg2 induced a hyperproliferative epidermal phenotype, increased apoptosis resistance of keratinocytes, and enhanced development of papillomas. Consistent with these observations, Dsg2 overexpression was also associated with deregulated epidermal signal transduction and upregulation of tumor-associated genes including the metastasis-associated proteins. These signaling components have previously been implicated in hyperproliferation and/or malignant transformation of epithelial cells and tissues. Based on this strong preliminary evidence we propose to molecularly define the pathways by which Dsg2 modulates epithelial cell fate. This goal will be pursued in two specific aims to: 1) determine the molecular mechanisms by which Dsg2 expression supports epithelial cell survival and proliferation, and 2) determine molecular mechanisms underlying increased susceptibility of Dsg2 Tg mice to skin tumorigenesis in vivo. Overall, the proposed studies will elucidate novel intracellular signaling roles of Dsg2 as they relate to skin structure, function, and carcinogenesis. [unreadable] Project Narrative/Relevance to Public Health: This application will help define the roles of desmosomal cadherins in modulating, not only epithelial cell-cell adhesion, but also cell growth and survival. In particular, we will focus on desmoglein 2, which is up regulated in several epithelia-derived cancers. Determining the molecular mechanisms by which desmoglein 2 affects tumor growth and development has the potential of identifying new targets for therapeutic cancer treatments. [unreadable] [unreadable] [unreadable]